1. Field of the Invention
The present invention relates to a process for the production of 4-alkylpyrimidines, particularly 4-methylpyrimidine.
2. Discussion of the Background
4-Methylpyrimidine is an intermediate for the synthesis of biologically active substances, such as e.g. plant protection agents or pharmaceuticals. Bredereck et al. developed syntheses for producing 1,3-diazoles starting from 1,3-dicarbonyl compounds and formamidine (Angew. Chem. 1956, 68, 151; Chem. Ber. 1957, 90, 942). According to a synthesis by Bredereck et al. (Org. Synth. Coll. Vol. V, 794, Wiley 1973), formamide can be reacted with 4,4-dimethoxy-2-butanone (formyl acetone dimethylacetal) in the presence of ammonium chloride and water at 180–190° C. to form 4-methylpyrimidine as follows:

The above method has a number of disadvantages. On hand, the yield is modest by industrial standards, at 54–63%. On the other hand, to achieve the yield at all, an excess of formamide of 6:1 has to be used, based on 4,4-dimethoxy-2-butanone, although only 2 moles are needed. In addition, it is necessary to add a slightly acidic catalyst at 30 mole %, based on 4,4-dimethoxy-2-butanone. During the subsequent distillation, ammonium salts sublime into the gas space and precipitate at a cooler point in the reaction apparatus, which is a great problem on an industrial scale as these salts can, for example, clog up reactor condensers and lead to production failures. The workup of the distillate, which is conventional in the Bredereck method, utilizes a lengthy extraction with chloroform to separate the 4-methylpyrimidine from the water of reaction and methanol. This inefficient operation is necessary because of the very good water solubility of 4-methylpyrimidine.
Other production methods for pyrimidines start from formamidinium salts, which has the disadvantage in principle that formamide generally has to be released by adding a base, conventionally an alkali alcoholate (e.g. sodium methylate) (e.g. JP 08198858, JP 49124081). In these process variants too, the yields that can be achieved are generally unsatisfactory. Thus, in a patent published only recently, a method is employed in which formamidinium acetate is used and then extraction is performed with tert-butyl methyl ether for a total of 20–26 h. The raw material obtainable in this way could be purified by distillation only with difficulty. Yields of 34 to 50% with contents of 95–98% were typical. In addition, mixed fractions were obtained with contents of 88 to 94%, which in turn contributed a further approx. 10% to the total yield (DE 10002835).